Tuesday, March 21, 2023
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Professor of Medicine
Harvard Medical School
Senior Physician
Cardiovascular Division
Brigham and Women's Hospital
Boston, Massachusetts
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Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™
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This activity is intended for diabetologists and endocrinologists, cardiologists, and primary care physicians.
The goal of this activity is for learners to be better able to interpret the practical implications of new data on the use of SGLT2 inhibitors in patients with type 2 diabetes (T2D) and cardiovascular disease (CVD), heart failure (HF), and/or chronic kidney disease (CKD).
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Medscape, LLC requires every individual in a position to control educational content to disclose all financial relationships with ineligible companies that have occurred within the past 24 months. Ineligible companies are organizations whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.
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Professor of Medicine
Harvard Medical School
Senior Physician
Cardiovascular Division
Brigham and Women's Hospital
Boston, Massachusetts
This activity has been peer reviewed and the reviewer has no relevant financial relationships.
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Medscape recently sat with Christopher Cannon, MD, Cardiologist at Brigham and Women's Hospital, and Professor of Medicine at Harvard Medical School to discuss the wealth of clinical evidence on sodium-glucose cotransporter 2 (SGLT2) inhibitors that was recently presented at 2 large European conferences -- European Society of Cardiology (ESC) 2022 and European Association for the Study of Diabetes (EASD) 2022. Dr Cannon shared his insights on these data and emphasized the need for physicians to use SGLT2 inhibitor therapy in appropriate patients in practice.
Medscape: What is your overall take on the data presented on SGLT2 inhibitors at the ESC 2022 and EASD 2022 meetings?
Dr Cannon: These 2 large meetings in Europe presented a wealth of new information, particularly on SGLT2 inhibition and heart failure (HF). Results from the large DELIVER trial in patients with HF with mildly reduced ejection fraction (HFmrEF) and HF with preserved ejection fraction (HFpEF) confirmed benefits that were also seen in the prior EMPEROR-Preserved trial. Numerous subgroup analyses and then meta-analyses were presented, which really firm up the observation that SGLT2 inhibition is a first-line therapy in HF regardless of the left ventricular ejection fraction (LVEF), which is reflected in recently updated HF guidelines.
Data on the use of these agents in chronic kidney disease (CKD) continue to emerge, with renal outcomes anticipated at upcoming meetings. A consensus was recently published on guidelines by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) on diabetes management in patients with CKD to reflect recent data. Furthermore, clinical data on the safety of SGLT2 inhibitors and their use as first-line agents in certain patients with type 2 diabetes (T2D) have been incorporated into the updated ADA/EASD T2D consensus that was also presented at EASD 2022.
It is now incumbent on all physicians to make sure appropriate patients are getting this evidence-based guideline-recommended therapy.
Medscape: Can you summarize how SGLT2 inhibitors work and their benefits demonstrated in cardiovascular outcomes trials (CVOTs)?
Dr Cannon: SGLT2 inhibitors are oral agents that were originally developed to treat hyperglycemia. They enhance glucose excretion in the urine, which achieves intermediate to high glycemic efficacy that is dependent on estimated glomerular filtration rate (eGFR) function.[1] These agents also reduce blood pressure and body weight regardless of eGFR.
All CVOTs of SGLT2 inhibitors have shown cardiovascular (CV) safety, and some agents significantly reduce major adverse CV events (MACE).[2] SGLT2 inhibitors produce consistent benefits in reducing hospitalization for HF (HHF) and kidney outcomes.[2] Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are another class of T2D agents that reduce MACE in addition to reducing blood pressure and lipids, with large reductions in body weight.[3-5] These agents do not reduce HHF, but they do reduce albuminuria with their effects on progression of CKD being investigated in ongoing trials.
Medscape: Why is reducing the risk of MACE, HF, and CKD critical in T2D management?
Dr Cannon: Cardiovascular disease (CVD) is the leading cause of death in patients with T2D,[6] and thus, CV risk assessment and providing cardiorenal protection have become a main focus of T2D guidelines.[1,6,7] Renal impairment and HF are common in patients with T2D, and they greatly increase CV risk.[1] Updated T2D recommendations present a holistic approach to management that goes beyond reducing glycemia to addressing multiple factors that contribute to CVD.[1] This paradigm shift in T2D management[8] is why new data on CV and renal protective agents are critical to identify populations who may reap benefit from their use; those with and even without T2D.
Medscape: Can you describe the results of the DELIVER trial and subgroup analyses that were presented at ESC 2022 and simultaneously published?
Dr Cannon: DELIVER enrolled a large, broad population (n = 6263) of high-risk patients with HFmrEF (ejection fraction [EF]: 41%-49%) and HFpEF (EF: ≥ 50%).[9] Notably, about half of participants did not have T2D. In DELIVER trial, dapagliflozin showed a significant 18% reduction in the primary composite endpoint of worsening HF and CV death, a significant 21% reduction in worsening HF alone (Figure 1), and a nonsignificant 12% reduction in CV death vs placebo with similar benefit based on LVEF or T2D history.[9]
Figure 1. Incidence of the Composite Primary Outcome (A) and Worsening HF (B) From the DELIVER Trial[9]
Previously, dapagliflozin and empagliflozin demonstrated benefits in patients with HF with reduced ejection fraction (HFrEF) (EF < 40%) in the DAPA-HF trial[10] and EMPEROR-Reduced trial,[11] respectively, and these agents have become a standard of care in HFrEF.[12] The results of DELIVER trial extend the benefits of dapagliflozin to patients with LVEF of > 40% and are consistent with results of the EMPEROR-Preserved trial, which showed benefits of empagliflozin in patients with HFpEF.[13]
Numerous subanalyses of DELIVER trial were also presented at ESC showing similar CV efficacy and safety with dapagliflozin in patients with HFmrEF/HFpEF irrespective of the following at baseline:
Medscape: What meta-analyses were presented at ESC 2020, and what are their findings?
Dr Cannon: Three meta-analyses were presented that reinforce the consistent CV benefits of SGLT2 inhibition in patients with both HFrEF and HFmrEF/HFpEF, regardless of LVEF or T2D history.
DELIVER and EMPEROR-Preserved Trials
This prespecified meta-analysis evaluated 12,251 participants in the 2 HFpEF trials: DELIVER and EMPEROR-Preserved.[20] The results showed that SGLT2 inhibitors reduced the primary composite endpoint of CV death or first HHF by 20% vs placebo (HR: 0.80; 95% CI: 0.73, 0.87), with consistent reductions in both components: CV death (HR: 0.88; 95% CI: 0.77, 1.00) and first HHF (HR: 0.74; 95% CI: 0.67, 0.83). Results were consistent across 13 subgroups and across LVEFs (from > 40% to ≥ 60%).
Five Large Randomized Controlled Trials (RCTs) of SGLT2 Inhibitors in HF
This second analysis included > 20,000 participants with any type of HF in 5 RCTs of SGLT2 inhibitors in HF: DELIVER, EMPEROR-Preserved, DAPA-HF, EMPEROR-Reduced, and SOLOIST-WHF.[20] SGLT2 inhibitors showed reduction in all CV endpoints vs placebo across a broad range of patients with HF including both HFrEF and HFmrEF/HFpEF (Figure 2). The outcomes were generally consistent across all subgroups including the full range of LVEFs (< 40% to ≥ 60%) and T2D history. Importantly, CV and all-cause death were significantly reduced with SGLT2 inhibition.
Figure 2. Outcomes From a Meta-Analysis of 5 RCTs of SGLT2 Inhibitors in HF[20]
DELIVER and DAPA-HF
A patient-level pooled meta-analysis of 11,007 participants in the dapagliflozin HF program -- the DELIVER and DAPA-HF trials -- showed that dapagliflozin reduced the risk of all prespecified CV endpoints vs placebo with similar benefit across the range of LVEFs (< 40% to ≥ 60%).[21] Dapagliflozin significantly reduced CV death (HR: 0.86; 95% CI: 0.76, 0.97; P = .01), death from any cause (HR: 0.90; 95% CI: 0.82, 0.99; P = .03), total (first and repeat) HHF (rate ratio: 0.71; 95% CI: 0.65, 0.78; P < .001), and the MACE composite of CV death, myocardial infarction, or stroke (HR: 0.90; 95% CI: 0.81, 1.00; P = .045).
Collectively, these meta-analyses, in addition to data from CVOTs, confirm that SGLT2 inhibition should be used in patients with any type of HF regardless of T2D status.
Medscape: Were there data presented at EASD 2022 that coincide with the HF data from ESC 2022?
Dr Cannon: Yes, an analysis of another SGLT2 inhibitor, ertugliflozin, was presented at both ESC and EASD 2022, which demonstrated efficacy of this agent across the spectrum of LVEFs.[22,23] This analysis evaluated 5006 participants in the VERTIS-CV trial[24] who had available pretrial LVEF data ranging from ≤ 45% to > 60%. Ertugliflozin significantly reduced first HHF and total HHF consistently across all LVEFs (Figure 3).[22,23]
Figure 3. Efficacy of Ertugliflozin vs Placebo Across the Spectrum of LVEFs in VERTIS-CV[22,23]
P value for HR. †Interaction P value between pretrial LVEF. ERTU, ertugliflozin; PBO, placebo.
Another analysis presented at EASD 2022 evaluated the mechanisms of SGLT2 inhibition in the reduction of HHF. This analysis of 44 participants in the EMPA-HEART trial found that empagliflozin produced rapid and persistent improvement of left ventricular (LV) contractility in patients with subclinical systolic dysfunction (baseline LV global longitudinal strain of < 16.5%).[25] More randomized evidence on HF mechanisms is warranted.
Medscape: Can you summarize the effects of SGLT2 inhibitors on kidney outcomes and data presented at EASD 2022 on their use in CKD?
Dr Cannon: The CREDENCE trial was the first to show CV and renal benefits with canagliflozin in patients with T2D and CKD.[26] Similar to outcomes in HF, evidence from the DAPA-CKD trial showed kidney benefits with SGLT2 inhibition in patients with and without T2D.[27] Data from the EMPA-KIDNEY trial and renal endpoints from the DELIVER trial are anticipated at upcoming medical conferences this year;[28] both trials enrolled patients with and without T2D and with and without CKD at baseline. Also, KDIGO has recently announced that their 2012 CKD guidelines[29] will be updated to incorporate new evidence.[30]
An analysis of the EMPA-REG OUTCOME trial was presented at EASD 2022, which evaluated the effect of empagliflozin on inducing changes in KDIGO CKD risk group.[31] The results showed that empagliflozin was associated with a 30% lower odds of worsening in KDIGO CKD risk group (odds ratio [OR]: 0.70; 95% CI: 0.62, 0.78) and > 50% higher odds of improvement in KDIGO CKD risk group (OR: 1.56; 95% CI: 1.30, 1.86).
Medscape: What other relevant data were presented on SGLT2 inhibitors at either conference?
Dr Cannon: Real-world safety data were presented at ESC 2022, which showed that, although older adults (≥ 75 years) treated with SGLT2 inhibitors have higher rates than younger patients (as expected) for amputations, Fournier gangrene, diabetic ketoacidosis (DKA), genitourinary infections, and dehydration, the relative risk of these events with or without an SGLT2 inhibitor was similar between groups, with no new safety concerns.[32]
Adverse effects associated with SGLT2 inhibitors are genitourinary infections and DKA, both of which can be mitigated with proper patient education.[1] Furthermore, clinicians need to be aware of the initial dip in eGFR that is seen in most patients when starting an SGLT2 inhibitor but is subsequently linked to kidney protection; similar to that seen with renin-angiotensin-aldosterone system agents.[33]
At EASD 2022, results were presented on an RCT, which showed that, compared with placebo, ertugliflozin significantly reduced serum uric acid levels from baseline (HR: −0.0156; 95% CI: −0.0217, −0.0095; P < .001), with a nonsignificant reduction in gout-related outcomes (HR: 0.76; 95% CI: 0.580, 1.002; nominal P = .052) in patients with T2D and atherosclerotic CVD.[34]
Medscape: How have updated T2D and HF guidelines utilized these and other data to influence their recommendations?
Dr Cannon: The updated ADA/EASD T2D consensus was presented at EASD 2022. As supported by recent analyses,[35,36] SGLT2 inhibitors or GLP-1 RAs with proven cardiorenal protection are now considered first-line treatment, with or without metformin, in patients with T2D and cardiorenal disease or at high risk, regardless of glycemic control. This means, even if a patient with T2D with cardiorenal disease or at high risk has met their glycated hemoglobin target, they should still receive one of these agents, and SGLT2 inhibitors are preferred in patients with HF or CKD.[1]
The recent ADA/KDIGO consensus on diabetes management in patients with CKD also recommends an SGLT2 inhibitor with proven renal or CV benefit in patients with T2D, CKD, and eGFR of > 20 mL/min/1.73 m2, as first-line therapy regardless of glycemic control or metformin use.[37]
Recently updated HF guidelines consider SGLT2 inhibitors as 1 of the 4 first-line guideline-directed medical therapy options for patients with HFrEF, and these agents are now also recommended with a class 2a recommendation in HFmrEF and HFpEF (Table 1).[12]
Table 1. Recommendations for SGLT2 Inhibitors in Updated HF Guidelines by the American College of Cardiology/American Heart Association/Heart Failure Society of America[12]
|
Stage of HF |
Recommendation |
Class of Recommendation (COR) |
|---|---|---|
|
Stage A, at risk for HF (primary prevention) |
To prevent HHF in patients with T2D who have CVD or high CV risk |
1 |
|
Stage C, symptomatic HF |
||
|
HFrEF |
To reduce HHF and CV mortality in patients with symptomatic chronic HFrEF, regardless of presence of T2D |
1 |
|
HFpEF |
To reduce HHF and CV mortality in patients with HFpEF |
2a |
|
HFmrEF |
To reduce HHF and CV mortality in patients with HFmrEF |
2a |
Medscape: How should this new evidence and updated guidelines be translated to clinical practice?
Dr Cannon: With all this new evidence and updated guidelines directing us how and when to use SGLT2 inhibitors, it is now up to all of us physicians to implement these agents in our practice. The medical community needs to increase the use SGLT2 inhibitors to prevent cardiorenal disease; especially in patients with HF without diabetes, where using SGLT2 inhibition is a newer concept. My closing message is a call to action for all clinicians to be on the lookout for appropriate patients who may benefit from cardiorenal protection from SGLT2 inhibitors and to prescribe patients this beneficial treatment.
